1. Written informed consent.
2. Male or female between the ages of 18 and 75 years, inclusive, at Screening.
3. Meets the 2013 American College of Rheumatology/European League Against Rheumatism
classification criteria for SSc with a total score of ≥9 (Van den Hoogen et al.,
4. Classified as having skin involvement proximal to the elbow and knee (diffuse
cutaneous SSc subset by LeRoy and Medsger, 2001).
5. At the time of enrollment, less than 36 months since the onset of the first SSc
manifestation, other than Raynaud's phenomenon.
6. Based on data available through medical history and/or medical records, the subject
should have at least 1 of the following:
1. disease duration ≤18 months. 2. increase ≥3 in mRSS units compared with the last visit within the previous 1
month to 6 months. 3. involvement of 1 new body area with ≥2 mRSS units or 2 new body areas with ≥1
mRSS unit. 4. documentation of worsening skin thickening for subjects who did not have mRSS
performed during the previous visit. 5. presence of tendon friction rub at Screening. 7. Presence of at least 1 of the following features of elevated acute phase reactants at
- - high-sensitivity C-reactive protein (hsCRP) ≥0.6 mg/dL (≥6 mg/L),
- erythrocyte sedimentation rate (ESR) ≥28 mm/hr,
- platelet count ≥330 × 10^9/L (330,000/μL).
8. Skin thickening from SSc in the forearm suitable for repeat biopsy.
9. mRSS units ≥15 at Screening.
10. FVC ≥45% predicted at Screening, as determined by spirometry.
11. Willing and able to comply with the prescribed treatment protocol and evaluations for
the duration of the trial.
1. Positive for anti-centromere antibodies.
2. Diagnosed with sine scleroderma or limited cutaneous SSc.
3. Diagnosed with other autoimmune connective tissue diseases, except for fibromyalgia,
scleroderma-associated myopathy and secondary Sjogren's syndrome.
4. Scleroderma renal crisis diagnosed within 6 months of the Screening Visit.
5. Any of the following cardiovascular diseases:
1. uncontrolled, severe hypertension (≥160/100 mmHg) or persistent low blood
pressure (systolic blood pressure <90 mmHg) within 6 months of Screening,
2. myocardial infarction within 6 months of Screening,
3. unstable cardiac angina within 6 months of Screening.
6. DLCO <40% predicted (corrected for hemoglobin). If severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider
using a DLCO up to 6 months before the Screening Visit.
7. Pulmonary arterial hypertension (PAH) by right heart catheterization requiring
treatment with more than 1 oral PAH-approved therapy or any parenteral therapy.
Treatment is allowed for erectile dysfunction and/or Raynaud's phenomenon/digital
8. Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening
(topical steroids for dermatological conditions and inhaled/intranasal/intra-articular
steroids are allowed).
9. Use of any other non-steroid immunosuppressive agent, small biologic molecule,
cytotoxic or anti-fibrotic drug within 4 weeks of Screening, including
cyclophosphamide, azathioprine (Imuran®) or other immunosuppressive or cytotoxic
medication. Exceptions include mycophenolate mofetil (CellCept®), mycophenolic acid
(Myfortic®), methotrexate and low-dose prednisone, as follows: use of CellCept ≤3
g/day, Myfortic ≤2.14 g/day, methotrexate ≤15 mg/week and prednisone ≤10 mg/day (or
equivalent dosing of glucocorticoids) is allowed. See Table 9.1 for full details.
Subjects taking CellCept, Myfortic or methotrexate must have been doing so for ≥6
months and the dose must have been stable for ≥16 weeks prior to the Day 1 Visit.
Prednisone must have been at a stable dose for ≥8 weeks prior to the Day 1 Visit. It
is acceptable to be on background low-dose prednisone and anti-malarial drug along
with CellCept, Myfortic or methotrexate. Rituximab must not have been used within 6
months of the Day 1 Visit.
10. Known active bacterial, viral, fungal, mycobacterial or other infection, including
tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are
11. Use of a United States Food and Drug Administration-approved agent for SSc or an
investigational agent for any condition within 90 days or 5 half-lives, whichever is
longer, prior to Screening or anticipated use during the course of the trial.
12. Malignant condition in the past 5 years (except successfully treated basal/squamous
cell carcinoma of the skin or cervical cancer in situ).
13. Women of childbearing potential or male subjects not agreeing to use highly effective
method(s) of birth control throughout the trial and for 1 month after last dose of
trial drug. Male subjects must refrain from sperm donation and females from egg/ova
donation for this same time period.
14. Pregnant or lactating women.
15. Current drug or alcohol abuse or history of either within the previous 2 years, in the
opinion of the Investigator or as reported by the subject.
16. Previous enrollment in this trial or participation in a prior HZN-825 or SAR100842
17. Known history of positive test for human immunodeficiency virus.
18. Active hepatitis (hepatitis B: positive hepatitis B surface antigen and positive
anti-hepatitis B core antibody [anti-HBcAb] and negative hepatitis B surface antibody
[HBsAb] or positive for HBcAb with a positive test for HBsAb and with presence of
hepatitis B virus DNA at Screening; hepatitis C: positive anti-hepatitis C virus
[anti-HCV] and positive RNA HCV).
19. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing
20. Previous organ transplant (including allogeneic and autologous marrow transplant).
21. International normalized ratio >2, prolonged prothrombin time >1.5 × the upper limit
of normal (ULN) or partial thromboplastin time >1.5 × ULN at Screening.
22. Alanine aminotransferase or aspartate aminotransferase >2 × ULN.
23. Estimated glomerular filtration rate <30 mL/min/1.73 m^2 at Screening.
24. Total bilirubin >2 × ULN. Subjects with documented diagnosis of Gilbert's syndrome may
be enrolled if their total bilirubin is ≤3.0 mg/dL.
25. Any other condition that, in the opinion of the Investigator, would preclude
enrollment in the trial.